Alkyl esters of 1-(p-thiolsulfophenyl)-2-acylamido-1, 3-propanediols and their preparation



United States Patent ALKYL ESTERS 0F l-(p-THIOLSULFOPHENYL)-2- ACYLAMIDO-LS-PROPANEDIOIS AND THEIR PREPARATION Walter A. Gregory, Wilmington, DeL, assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Application September 24, 1953, Serial No. 382,195

Claims. 01. 260-453) where R is an aliphatic radical of the group consisting of alkyl, allyl, hydroxyethyl and carboxymethyl radicals. Acyl represents a radical. such as acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, dibromoacetyl and the like.

Included among the compounds represented by Formula 1, which are preferred, are those wherein R is an alkyl or alkenyl radical having not more than 18 carbon atoms, said alkenyl radical being attached to sulfur thru a methylene group. Still more preferred are compounds of Formula 1 where R is a lower alkyl radical.

For purposes of this invention the aliphatic radical, R, can carry substituent groups. Thus, for example, R can represent fl-hydroxyethyl, carboxymethyl and like radicals.

Illustrative of the alkyl esters of l-(p-thiolsulfophenyD- Z-acylarnido-l,3-pr0panediols of the present invention are:

1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido) -1,3-propanediol, methyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-l,3-propanediol, ethyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido) -l,3-propanediol, n-propyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-1,3-propanediol, isopropyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-1,3-propanediol, n-butyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-l,3-propanediol, isobutyl ester 1 (p-thiolsulfophenyl) 2 (alpha,a1pha dichloroacetamido)-l,3-propanediol, t-butyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-l,3-propanediol, dodecyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-l,3-propanediol, beta-hydroxy ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-1,3-propanediol, carboxymethyl ester 1 (p-thiolsulfophenyl) 2 (alpha,alpha dichloroacetamido)-1,3-propanediol, allyl ester l-(p-thiolsulfophenyl) 2 acetamido 1,3 propanediol,

methyl ester l-(p-thiolsulfophenyl) 2 (alpha-chloroacetamido)-1,3-

propanediol, ethyl ester l-(p-thiolsulfophenyl) 2 (alpha,alpha dibromoacetamido)-l,3-propanediol, methyl ester The compounds of the invention can be prepared from previously known organic compounds by a novel method which I have discovered.

All of the compounds represented by Formula 1 may exist in optical isomeric form. Stereoisomeric forms used herein refer to the spatial arrangement of the polar groups on the two asymmetric carbon atoms with reference erythrose and threose. To differentiate between these two possible forms the convention will be employed which designates the diastereoisomeric pair related to erythrose in configuration as the erythro form, and the diastereoisomeric pair related to threose as the threo form.

To further designate the threo form of the compounds of the invention, I have designated as the threo form the major product obtained from the aluminum isopropoxide-isopropyl alcohol reduction of the ketones of the formula 2. O NH-Aoyl where acyl has the same significance as in Formula 1.

Both the threo and erythro forms exist as racemates of optically active dextro (d) and levo (l) rotatory isomers as well as in the form of the individual or separated dextro (d) and levo (1) optical isomers.

In view of the difficulty of representing the various optical isomers with plane formulas, I have used the customary structural formulas and adopted the following convention in order to designate their optical configuration, and appropriate notation is used under the formula, for example, (l)-threo form, (d)-threo form, (l)-erythro form, (d)-erythro form, (dl)-threo form and the like.

It will be understood that where no notation appears with a structural formula or with a chemical name, the formula or name is to be interpreted in its generic sense; that is, as representing the (d)-threo, (l)-threo isomers or (d)-erythro, (l)-erythro isomers in separated form as well as the (cll)-threo or (dl)-erythro optical racemates. In other words, a formula or name represents not only the unresolved mixture of isomers but also the individual isomers and racemates.

The compounds of the present invention can be prepared by any of several different methods.

My preferred method involves the preparation of an aqueous solution of an alkali metal salt of l-(p-thiolsulfophenyl)-2-acylamido-1,3-propanediol by reacting l-(pfluorosulfonylphenyl)-2-acylamido- 1,3 -propanediol with an aklali metal sulfide such as, for instance sodium sulfide, in an aqueous solution and preferably in the absence of oxygen.

The above reaction proceeds in two steps and may be shown by the following equation:

It is preferred to use an excess of the alkali metal sulfide, say, for example, from about 1% to 3 mols of M28 for each mol of the 1-fiuorosulfonylphenyl-Z-acylamidol,3 propanediol.

The resulting aqueous solution of the alkali metal salt of l-(p-thiosulfophenyl)-2-acylamido 1,3 propanediol is then treated with an appropriate alkylating agent such as alkyl halides, allyl halides, ethylene halohydrins, haloacetic acid salts, or dialkyl sulfates. The amount of alkylating agent used is preferably in excess of the theoretical amount required to react with the l-p-thiosulfophenyl-Z-acylamido-1,3-propanediol.

The alkylation reaction is represented graphically by the following equation:

To avoid undesired side reactions the alkylation step is carried out at a temperature in the range from about 10 to 40 C. The alkylating agent may be added in an inert solvent such as dioxane, tetrahydrofuran, dimethyl formamide or an alcohol such as methanol or ethanol.

Alternatively, the compounds of the invention can be prepared by reacting in an inert liquid medium an alkali or alkaline earth metal alkyl mercaptide with (a) l-(pfiuorosulfonylphenyl)-2-amino-l,3-propanediol having the formula 3. OH NH,

F sQd-CH= The synthesis involves the following sequence of steps: halogenation, addition of hexamethylenetetramine, treatment with $02 and water, HC] treatment, acylation, treatment with formaldehyde in the presence of a weak inorganic case, and a Meerwein-Ponndorf-Verly reduction or alternatively a NaH4B reduction.

Compounds represented by Formula 4 are readily available from either of two types of chemical structures, namely,

Potassium permanganate and magnesium nitrate may be used to convert a compound of Formula 5 to a compound of Formula 4. Compounds of Formula 6 can be converted to those of Formula 4 by use of potassium fluoride and water.

The conversion of 1-(p-fiuorosulfonylphenyl)-2-acylamidO-L3-propanediol to the free amine represented by Formula 3 is described, as already mentioned, in my copending application Serial No. 309,734, filed concurrently herewith, now abandoned. This conversion is effected by refluxing an aqueous mixture of a l-(p-fiuorosulfonylphenyl)-2acylamido-l,3-propancdiol corresponding to a continuation-in-part of all] 4 Formula 3 with hydrochloric acid. This results in the production of the corresponding fiuorosulfonylphenyl amino propanediol hydrochloride.

In the alternative and less preferred process employing the free amino compound or a salt thereof it will be understood that care should be exercised to prevent the interaction of the fiuorosulfonyl group with the amino group.

The fluorosulfonylphenyl amino propanediol hydrochloride can be reacted in an inert liquid medium with the alkali or alkaline earth metal mercaptide corresponding to the formula 7. M(SR)n where M is an alkali or alkaline earth metal, 12 is the valence of the metal M and R has the same significance as in Formula 1 to produce compounds which can be acylated to give the products of this invention corresponding to Formula 1 above. When employing the hydrochloride, two chemical equivalents of the metal mercaptide corresponding to Formula 7 above are employed for each mole of the fiuorosulfonylphenyl amino propancdiol hydrochloride.

It is preferred to add the fiuorosulfonylphenyl amino propanediol hydrochloride in solution or in suspension in an inert liquid medium to a solution of the metal mercaptide in an aliphatic alcohol having no more than four carbon atoms.

When employing the free amine corresponding to Formula 3 above the reaction is most conveniently carried out by neutralizing an aqueous solution of the hydrochloride with, for example, aqueous sodium hydroxide followed by immediate addition of the liberated fluorosulfonylphenyl amino propanediol to a solution of the metal mercaptide in an aliphatic alcohol of no more than four carbon atoms.

The final step of my alternative process involves acylating an alkyl ester of l-(p-thiolsulfophenyl)2-amino-l,3- propanediol. Any of a variety of acylating agents may be employed. There may be used, for instance, methyl acetate, methyl chloroacetate, methyl bromoacetate and methyl dibromoacetate. Methyl dichloroacetate is preferred.

The compounds of the present invention are useful as drugs for the control of bacteria and rickettsial infections. They may also find use in the control of viral and fungal infections. The compounds find further use as antibacterial agents and for the control of growth of microorganisms such as yeast and fungi.

In order to better understand the invention, reference should be had to the following illustrative examples:

Example 1 Preparation of (dl)-threo-l-(p-thiolsulfophenyl)-2- (alpha,alpha-dichloroacetarnido)-1,3-propanediol, methyl ester.

A suspension of 36 g. of (dl)-threo-l-(p-fluorosulfonylphenyl -2-(alpha,alpha-dichloroacetamido) -1 ,3 propanediol in 50 cc. of water containing 36 g. of sodium monosulfide monahydrate is stirred under a nitrogen atmosphere at C. until the solid has dissolved, and then for about 3 hours longer. The solution contains the sodium salt of (dl) threo 1 (p thiolsulfophenyl) -2- (alpha-alpha-dichloroacetamido)1,3-propanediol which has the structure:

OH NHC OCHOla The solution is cooled to 10 C. and 15 g. of dimethyl sulfate is added with good agitation. The temperature of the reaction mixture is kept below 15 C. The reaction is allowed to continue for a period of about one hour. The solution is extracted repeatedly with ethyl acetate.

The product crystallizes from the extract after concentrating under reduced pressure. The product is a white crystalline solid and has the formula OH NHCOOHOII CHsS-SOr-GH-H-OEHOH Example 2 (dl)-Threo 1 (p-thiolsnlfophenyl)-2-(alpha,alpha-dichloroacetamido)-1,3-propanediol, ethyl ester.

A solution of the sodium salt of (dl)-threo-1-(p-thiolsulfophenyl) 2 (alpha alpha dichloroacetamido)1 3- propanediol is prepared as shown in Example 1. To this solution there is added 22 g. of ethyl iodide with rapid stirring. The temperature of the reaction mixture is maintained between 10-15 C. The reaction is continued for a period of about two hours and the resulting solution is concentrated under reduced pressure. The residue is extracted with boiling ethanol. The product is isolated as white crystals by concentrating the alcohol extract. The product has the formula OH NHOOGHCI:

Example 3 Preparation of (dl)-threo-l-(p-thiolsulfophenyl)-2- (alpha,alpha-dichloroacetamido) 1,3 propanediol, isopropyl ester.

A solution of the sodium salt of (dl)-threo-l-(p-thiolsulfophenyl) 2 (alpha, alpha dichloroacetamido)-1,3- propanediol is prepared as shown in Example 1.

The solution is cooled to a temperature of 10 C. and 25 g. of isopropyl iodide is then added. The temperature of the reaction mixture is maintained between 10-15 C. for a period of three hours. The solution is stirred vigorously during the three hour period and then is allowed to warm to room temperature. It is stirred for an additional period of two hours.

The solution is concentrated under reduced pressure. The non-volatile residue is extracted with boiling ethanol. The product is obtained from the extracts by concentrating. The product is a white crystalline solid having the following structure:

on. OK NHoocHcn onssoi-@ en-cnomon C Example 4 Preparation of (dl)-threo 1 (p thiolsulfophenyl)-2- (alpha,alpha-dichloroacetamido) 1,3 -propanediol, allyl ester.

A solution containing the potassium salt of (db-threelp-thiosulfophenyl -2- alpha,alpllra-dichloroacetamido) 1,3-propanedil is prepared in a manner similar to that shown in Example 1. This solution is cooled to C. and a solution of 11.4 g. of allyl chloride in 200 cc. of dioxane is added with stirring under a nitrogen atmosphere. The temperature of the reaction mixture is maintained at from 10-15 C. during the addition of the allyl chloride. Stirring is continued after the addition is complete for a period of about three hours and the solution is then allowed to warm to room temperature. After concentrating the solution under reduced pressure the residue is extracted with hot methanol. The methanol extracts are concentrated to give a white crystalline compound having the structure 011 NHCOOHCI:

Example 5 (dl)-Threo 1(p-thiolsulfophenyl) 2 (alpha,alpha-didhloroacetamido)-l,3-propanediol, beta-hydroxyethyl ester.

A solution containing the sodium salt of (dD-threo- 1- (p-thiosulfophenyl -2-alpha,alpha dichloroacetamido) 1,3-propanedilol is prepared as shown in Example 1. This is cooled to 10 C. and 20 g. of ethylene iodohydrin is added slowly. The temperature of the reaction mixture is kept between 10-l5 C. The mixture is stirred for three hours and then warmed to 30 C. and stirred for two hours.

The product is isolated by concentrating the solution under reduced pressure and extracting the residue with hot methanol. The product is a white crystalline solid which has the structure 0H NHOOCHCI:

Hoon,on,-s-sor-@oncH-on,orr

Example 6 Preparation of (dl)-threol (p-thiolsulfophenyl)-2- (alphaalpha-dichloroacetamido} 1,3 propanediol, carboxymethy l ester.

A solution of the sodium salt of (dl)-threo-1-(p-thiolsulfophenyl -2-( alpha,a1pha dichloroacctamido)-1,3-propanediol is prepared \as shown in Example 1. After cooling the solution to 10 C. a solution consisting of 20 g. of sodium brornoacetate in 25 cc. of water is added slowly while stirring in a nitrogen atmosphere. The temperature of the reaction mixture is held between 10-l5 C. for a period of three hours, then warmed to 30 C. for a period of one hour.

The solution was concentrated under reduced pressure and the residue diluted with water, made acid with dilute hydrochloric acid and again concentrated. The residue is extracted with hot ethyl acetate.

The product is obtained from the extracts by concentrating under reduced pressure. The product has the following structural formula:

OH NHCOCHCI:

Example 7 Preparation of (dl -threol (p-thiosulfophenyl) -2-aoetamidol,3-propanediol, methyl ester.

A suspension of 36 g. of (dl)-threo-1(p-fluorosulfonylphenyl)-2-acetamido-1,3-pnopanediol in 50 cc. of water containing 36 g. of sodium monosulfide monohydrate is stirred under a nitrogen atmosphere at 30 C. until the solid has dissolved, and then for about 3 hours longer. The solution contains the sodium salt of (d!)- threo 1 (p-thiolsulfophenyl)-2-acetamido-l,3-propanediol which has the structure:

011 NHC OCHi The solution is cooled to 10 C. and 15 g. of dimethyl sulfate is added with good agitation. The temperature of the reaction mixture is kept below 15 C. The reaction is allowed to continue for a period of about one hour. The solution is extracted repeatedly with ethyl acetate.

The product recrystallizes from the extract after concentrating under reduced pressure. The product is a white crystalline solid and has the formula OH NHCOCH;

7 I claim: 1. A compound having the formula where R is an aliphatic radical of the group consisting of alkyl, allyl, hydroxyethyl and carboxymethyl radicals and acyl is a member of the group consisting of acetyl, chloroacetyl, bromoacetyl, dichloroacetyl and dibromoacetyl radicals.

2. A compound having the formula OH NHCOCHCh where R is a lower alkyl group.

3. (dl) Threo l (p thiolsulfophenyl) 2 (alpha,- alpha-dichloroacetamido)-l,3-propanediol, methyl ester.

4. (dl)-Threo l (p-thiolsulfophenyl)-2-(alpha,alphadichloroacetamido)-l,3-propanediol, ethyl ester.

5. (JD-Three l (p-thiolsulfophe-nyl)-2-(alpha,alphadichloroacetamido)-l,3-propanediol, isopropyl ester.

6. (dl)-Threo l (p-thiolsulfophenyl)-2-(alpha;alphadiehloroacetamido) 1,3-propanediol, beta-hydroxyethyl ester.

7. (db-Three l (p-thiolsulfophenyl)-2- (alpha;alphadichloroacetamido)-l,3-propanediol, allyl ester.

8. In a process for preparing a compound of the formula OH NH-Acyl where R is an aliphatic radical of the group consisting of alkyl, allyl, hydroxyethyl and carboxymethyl radicals and acyl is a member of the group consisting of acetyl, chloroacety], bromoacetyl, dichloroacetyl and dibromoacetyl radicals, the steps comprising reacting l-(p-fluorosulfonylphenyl)-2-acylarnid01,3-propanediol with an alkali metal sulfide in an aqueous medium and reacting the resulting alkali metal salt of l-(p-thiolsulfophenyl)-2- acylamido-1,3-propanediol at a temperature of from about 10 to C. with an alkylating agent of the class consisting of alkyl halides, allyl halides, ethylene halohydrins, haloacetic acid salts, and dialkyl sulfates.

9. In a process for preparing a lower alkyl ester of l (p thiolsulfophenyl)-2-(alpha, alpha-dichloroacetarnido) 1,3-propanediol, the steps comprising reacting l-(pfluorosulfonylphenyl)-2-acylamido-l,3 propanediol with an alkali metal sulfide in the presence of water and alkylating the resulting aqueous solution of the alkali metal salt of l-(p-thiolsulfophenyl)-2-acylamido-1,3-propanediol with an agent of the class consisting of alkyl halides and dialkyl sulfates at a temperature of from 10 to 40 C.

10. In a process for preparing (d1)-threo-1-(p-thiolsu1- fophenyl)-2-(alpha,alpha-dichloroacetamido) 1,3 propanediol, methyl ester, the steps comprising reacting (dl) threo-l-(p-fluorosulfonylphenyl)-2-(alpha,alphadichloroacetamido)-l,3-propanediol with sodium sulfide in the presence of water to produce an aqueous solution of the sodium salt of (d!)-threo-l-(p-thiolsulfophenyD- 2- (alpha,alpha-dichloroacetarnido) l ,3-propanediol, and alkylating the latter compound with dimethyl sulfate at a temperature from 10 to 40 C.

Cutler et al.: J. A. C. 8., vol. 74, p. 5475 (November 1952). (Received for publication June 2, 1952.) 

1. A COMPOUND HAVING THE FORMULA
 8. IN A PROCESS FOR PREPARAING A COMPOUND OF THE FORMULA 